A. Background Regarding Nanoparticulate Active Agent Compositions
Nanoparticulate active agent compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles consisting of a poorly soluble therapeutic or diagnostic agent having associated with the surface thereof a non-crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate glipizide compositions.
Methods of making nanoparticulate active agent compositions are described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for “Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.” These patents do not describe methods of making nanoparticulate glipizide.
Nanoparticulate active agent compositions are also described, for example, in U.S. Pat. No. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat. No. 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” U.S. Pat. No. 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” U.S. Pat. No. 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” U.S. Pat. No. 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;” U.S. Pat. No. 5,349,957 for “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;” U.S. Pat. No. 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. Nos. 5,399,363 and 5,494,683, both for “Surface Modified Anticancer Nanoparticles;” U.S. Pat. No. 5,401,492 for “Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;” U.S. Pat. No. 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” U.S. Pat. No. 5,447,710 for “Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” U.S. Pat. No. 5,451,393 for “X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,466,440 for “Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;” U.S. Pat. No. 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,500,204 for “Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,518,738 for “Nanoparticulate NSAID Formulations;” U.S. Pat. No. 5,521,218 for “Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;” U.S. Pat. No. 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,543,133 for “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;” U.S. Pat. No. 5,552,160 for “Surface Modified NSAID Nanoparticles;” U.S. Pat. No. 5,560,931 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,565,188 for “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;” U.S. Pat. No. 5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;” U.S. Pat. No. 5,571,536 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” U.S. Pat. No. 5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” U.S. Pat. No. 5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective Overcoats;” U.S. Pat. No. 5,580,579 for “Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” U.S. Pat. No. 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;” U.S. Pat. No. 5,587,143 for “Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;” U.S. Pat. No. 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” U.S. Pat. No. 5,593,657 for “Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;” U.S. Pat. No. 5,622,938 for “Sugar Based Surfactant for Nanocrystals;” U.S. Pat. No. 5,628,981 for “Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;” U.S. Pat. No. 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,919 for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions;” U.S. Pat. No. 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” U.S. Pat. No. 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” U.S. Pat. No. 6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen;” U.S. Pat. No. 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen;” U.S. Pat. No. 6,221,400 for “Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;” U.S. Pat. No. 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” U.S. Pat. No. 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;” U.S. Pat. No. 6,270,806 for “Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;” U.S. Pat. No. 6,316,029 for “Rapidly Disintegrating Solid Oral Dosage Form,” U.S. Pat. No. 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” U.S. Pat. No. 6,428,814 for “Bioadhesive nanoparticulate compositions having cationic surface stabilizers;” U.S. Pat. No. 6,431,478 for “Small Scale Mill;” U.S. Pat. No. 6,432,381 for “Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract,” and U.S. Pat. No. 6,592,903 for “Nanoparticulate Dispersions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate,” all of which are specifically incorporated by reference. In addition, U.S. Patent Application No. 20020012675 A1, published on Jan. 31, 2002, for “Controlled Release Nanoparticulate Compositions,” and WO 02/098565 for “System and Method for Milling Materials,” describe nanoparticulate active agent compositions, and are specifically incorporated by reference. None of these references describe nanoparticulate glipizide compositions.
Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” U.S. Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” U.S. Pat. No. 5,741,522 for “Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and U.S. Pat. No. 5,776,496, for “Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.” These references do not describe nanoparticulate glipizide.
B. Background Regarding Glipizide
Glipizide is a sulfonylurea antidiabetic drug, first described in U.S. Pat. No. 3,669,966 issued on Jun. 13, 1972, to Carlos Erba S.P.A. The '966 patent claims are directed to chemical compounds and processes for preparing the sulfonyl urea drugs.
Glipizide is used to treat type 2 (noninsulin-dependent) diabetes (formerly known as “adult-onset” diabetes), particularly in people whose diabetes cannot be controlled by diet alone. Glipizide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be capable of producing insulin for this medication to work. The drug is marketed under the trade names Glucotrol (Pfizer, Inc.).
Glipizide is a crystalline solid that melts at 208-209° C. when crystallized from ethanol. The compound has the chemical name 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl]-phenyl]sulfonyl]urea, the chemical formula C21H27N5O4S, and the following chemical structure:

Peak plasma concentrations of conventional glipizide occur 1-3 hours after a single oral dose. Physicians' Desk Reference, 57th Edition, p. 2606-7. Total absorption of an oral dose is unaffected by food, but absorption is delayed by about 40 minutes. Thus, conventional forms of glipizide are more effective when administered about 30 minutes before a meal in diabetic subjects. Id.
Glipizide is indicated as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in subjects with non-insulin dependent diabetes mellitus (NIDDM; type II). Physicians' Desk Reference, 57th Edition, p. 2606-7.
The administration of oral hypoglycemic drugs has been shown to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. In addition, all sulfonylurea drugs are capable of producing severe hypoglycemia. Other potential adverse effects of glipizide include gastrointestinal disturbances, allergic skin reactions, leukopenia, agranolucytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, hepatic porphyria, and disulfiram-like reactions, and hyponatremia. Physicians' Desk Reference, 57th Edition, p. 2606-7.
U.S. Pat. No. 4,708,868 to Brickl et al., issued on Nov. 24, 1987, is directed to a method of preparing an oral antidiabetic pharmaceutical composition containing an antidiabetic sulfonyl urea as the active ingredient. The process comprises dissolving or emulsifying in an inert solvent in the presence of at least one solubilizing or emulsifying substance: (a) an acid antidiabetic sulfonyl urea with a basic excipient, or (b) an amphoteric antidiabetic sulfonyl urea with a basic or acid excipient, or (c) a basic antidiabetic sulfonyl urea with an acid excipient. Next, the resulting solution or emulsion is applied to the surface of a water-insoluble carrier, followed by drying the thus treated waster-insoluble carrier. Brickl et al. also claims the composition prepared by the recited process. Brickl et al. do not describe micron size or nanometer sized particles.
U.S. Pat. No. 6,464,988 to Gidwani et al., issued on Oct. 15, 2002, claims an inclusion complex of glipizide and a nonionic surfactant with a cyclodextrin or a cyclodextrin derivative, in combination with at least one pharmaceutically acceptable excipient. The glipizide is in micronized particle sizes of 1.0 to 40 μm and the cyclodextrin or cyclodextrin derivative is in particle sizes of 10 to 250 μm.
U.S. Pat. No. 6,555,139 to Sharma, issued on Apr. 29, 2003, claims a process for preparing a pharmaceutically active material having an average particle size of from about 1.0 to 15.0 micrometers. The process comprises microfludizing a composition comprising particles of a water-insoluble pharmaceutical material in an aqueous carrier liquid in the presence of at least 0.01% weight cyclodextrin particles.
U.S. Pat. No. 6,583,180 to Link et al., issued on Jun. 24, 2003, claims a method of treating a disease by administering a novel compound of Formula I as shown in the patent and an antidiabetic drug which can be glipizide.
U.S. Pat. No. 6,604,698 to Verhoff et al., issued on Aug. 12, 2003, claims a process for preparing a dispersion of solid particles of a milled substrate in a fluid carrier comprising the use of a combination of large and small milling media in a milling device.
None of the prior art patent references teach or suggest a nanoparticulate glipizide composition according to the present invention.
Glipizide has been used as an antidiabetic drug for several years, but absorption of the drug from tablets has been shown to be retarded due to delayed tablet disintegration and drug dissolution. See Wahlin-Boll et al., Clin. Pharmacokinet., July-August: 363-72 (1982). Thus, there is a need for glipizide in a form which achieves facile absorption.
There is a need in the art for glipizide compositions which can decrease frequency of dosing, improve bioavailability, improve clinical efficacy, and potentially reduce side effects. The present invention satisfies these needs.